This presentation discusses about the Acute liver failure in children, causes, etiopathogenesis, recent guidelines regarding management, recent evidence regarding role of N Acetyyl cysteine, Plasmapheresis, CRRT and newer modalities in ALF

1. Acute liver failure
Recent evidence
Presenter: Dr Siddan
Moderator: Dr Manas

2. Objectives
Introduction
Principle and mechanism
Equipment and Procedure
Indications
Prescription
Recent use in children and evidence
Other methods

3. Definition
SEVERE ACUTE LIVER INJURY (ALI)
• No underlying chronic liver disease*
• Liver damage
(serum aminotransferases 23x ULN)
• Impaired liver function
(jaundice and coagulopathy†) HEPATIC ENCEPHALOPATHY (HE)
Recent studies : HE Crucial for the
diagnosis of ALF . Mental alterations may
be initially subtle
Intensive screening at the first sign of HE
ALF
Up to 8 weeks post-jaundice,
other symptoms
• Acute onset of liver disease (<8weeks) without evidence of
chronic liver disease
• Biochemical evidence of severe liver injury
• Coagulopathy not corrected by vitamin K
• Prothrombin time (PT) 15 s or INR 1.5 with evidence of
hepatic encephalopathy or
• PT 20 s or INR >2 with or without encephalopathy
SEVERE ACUTE LIVER INJURY
HEPATIC ENCEPHALOPATHY
Non-essential component of
ALF
in children
ALF

4. Sub-classifications of ALF
1. O'Grady JG, et al. Lancet 1993;342:2735; 2. Bernal W, et al. Lancet 2010;376:190201;
EASL CPG ALF. J Hepatol 2017;66:1047–81
Weeks from development of jaundice to development of HE1
0 1wk 8wk 28wk
>28 weeks =
chronic liver
disease
Hyperacute1 Acute1 Subacute1
+++ ++ +
Severity of
coagulopathy2
+ ++ +++ Severity of jaundice2
++ ++ +/-
Degree of intracranial
hypertension2
Good Moderate Poor
Chance of spontaneous
recovery2
Paracetamol
HAV, HEV
Wilson
HAV, HBV, Non-
paracetamol drug-
induced, Tropical
infections, Wilson
Wilson disease, HBV Typical cause2
+++ High severity; ++ Medium severity; + Low severity; +/- Present or absent

5. Trend of ALF definition

6. Aetiology
Unknown
Paracetamol
Drug-related
Autoimmune hepatitis
Hepatitis A
Viral (not B)
Shock
Wilson disease
Metabolic
Other
ALF
Viral
Most common aetiology
in Asia and South America
Drugs
Paracetamol
Indeterminate
Around 50% of cases in
Europe and USA tend to
have severe disease and a
high fatality rate without
LTx. ~10% of these
patients develop bone
marrow failure
Neonatal
Gestational alloimmune liver disease
(neonatal haemochromatosis)
Other
Haemophagocytic
lymphohistiocytosis
Autoimmune
Mitochondrial
hepatopathy
Metabolic disease
e.g. Wilson disease

7. Infective cause- Look beyond hepatitis viruses
Herpesvirus and adenovirus – not to be missed

8. DILI – Why only antitubercular are culprit?
Cause unknown – look for drugs including parents
Even AMOXICLAV is can be culprit
Rodenticide toxicity - much more common cause of
ALF in India than paracetamol hepatotoxicity

9. Epidemiology
Bangladesh
HAV and HEV 75%
HBV 13%
Unknown 6%
Germany
Other causes* 28%
Unknown 21%
HBV 18%
India
HAV and HEV 44%
Unknown 31%
HBV 15%
Japan
HBV 42%
Unknown 34%
Other drugs 9%
Sudan
Unknown 38%
Other causes* 27%
HBV 22%
UK
Paracetamol 57%
Unknown 17%
Other drugs 11%
USA
Paracetamol 39%
Other causes* 19%
Unknown 18%

10. Pathophysiology

11. Laboratory diagnosis
Laboratory analyses at admission
Test for complications
• Lipase or amylase
Check aetiology
• Toxicology screen in urine and
paracetamol serum level
• Viral serological screen
– HBsAg, anti-HBc IgM (HBV DNA),
HDV if positive for HBV
– anti HAV IgM
– anti-HEV IgM
– anti-HSV IgM, anti-VZV IgM,
CMV, HSV, EBV, parvovirus and
VZV PCR
• Autoimmune markers‡
Assess disease severity
• PT, INR or factor V and full
coagulation screen
• Liver blood tests*
• Renal function
– Urine output: hourly
– Urea†
– Creatinine may be difficult to
assay in the context of elevated
bilirubin
• Arterial blood gas and lactate
• Arterial ammonia

12. Organ-specific concerns and management
EASL CPG ALF. J Hepatol 2017;66:1047–81
Main organ-specific complications in ALF
Coagulation/haemostasis
Unbalanced haemostasis
Thrombocytopenia
Infection
Bacterial, fungal
Pneumonia
Septicaemia
Urinary infection
Haemodynamic
Hyperkinetic syndrome
Arrhythmia
Neurological = cerebral oedema
Acute liver failure
Pulmonary
Pneumopathy
Acute respiratory distress syndrome
Pulmonary overload
Cranial hypertension
Brain death
Metabolic
Hypoglycaemia
Hyponatraemia
Hypophosphataemia
Hypokalaemia
Renal
Toxic
Functional

13. Fluids management
• The goal of fluid balance is to maintain hydration and renal function without worsening or provoking cerebral edema
• Fluid input should be 75% to 95% of normal maintenance
• Hypoglycemia detrimental
• Sodium- a double edged sword
• Lactate – Not everything is shock
Recommendations
Stringent attention to detail and normalization of biochemical abnormalities is warranted in patients
with ALF
III 1
Hypoglycaemia is common in patients with ALF, is associated with increased mortality and needs to
be corrected avoiding hyperglycaemia
II-3 1
In case of cerebral oedema should be corrected to maintain concentrations 140–150 mmol/L II-2 1
Treat hyponatremia when patient is symptomatic or Na <120 and avoid sustained
hypernatremia
Lactate elevation is related to increased production and decreased clearance, and remains a poor
prognostic marker. RRT is indicated to correct acidosis and metabolic disturbances
II-3 1

14. Ventilation in Liver failure
Indications
• Encephalopathy
• Hepatopulmonary syndrome
• Massive ascites
• ARDS
Concerns while intubation
• Physiological difficult airway
• High risk of aspiration
• Profound hypoxemia if delayed
• Cardiac dysfunction
Concerns while ventilation
Cis atracurium as NMB during intubation
Minimal sedation Fentanyl and propofol
Higher PEEP if gross ascites
preferred for sedation
Strict control of CO2
Balance risk vs benefit for PPI
State of relative immunosuppression
ARDS
SAY NO TO BENZODIAZEPINE…….

15. Cardiovascular
• Most patients presenting with ALF or severe ALI develop systemic vasodilation with reduced effective
central blood volume
• Central venous pressure monitoring is helpful for assessing and maintaining organ perfusion
• Hyperdynamic circulation with wide pulse pressure
• Fluid status assessment difficult
Recommendations
Most patients are volume depleted at presentation and require crystalloid volume
resuscitation
II-1 1
Persistent hypotension requires critical care management, with application of vasopressive
agents guided by appropriate monitoring techniques
II-3 1
Noradrenaline is the vasopressor of choice III 1
Volume overload is as detrimental as underfilling II-2 1
Hypoxic hepatitis will require consideration of inotropic agents II-3 1
A blood pressure target has not been defined in the literature III 2
Hydrocortisone therapy does not reduce mortality but does decrease vasopressor
requirements
II-1 1

16. Hepatic encephalopathy
 Remember frequent assessment is key – imaging doesn’t help
 CT head - to evaluate intracranial herniation or intracranial bleeding but is not sensitive to the degree of cerebral edema
 NIRS correlates with risk for neurologic complications

17. Rifaximin helps early resolution
What need to be used? Is it cocktail?
Combination with lactulose – better
PEG leads to a higher drop in the HESA Score and thus leads to a faster resolution of
HE compared with lactulose

18. Recommendations
Patients with low-grade encephalopathy should be frequently evaluated for signs of worsening encephalopathy
III 1
In patients with grade 3 or 4 encephalopathy, intubation should be undertaken to provide a safe environment
and prevention of aspiration. Regular evaluation for signs of intracranial hypertension should be performed III 1
Transcranial Doppler and NIRS are useful non-invasive monitoring tool II-3 1
Invasive intracranial pressure monitoring should be considered in patients who have progressed to grade 3 or 4
coma, are intubated and ventilated, and deemed at high risk of ICH, based on the presence of >1 of the
following variables:
• Young patients with hyperacute or acute presentations
• Ammonia level over 150–200 μmol/L that does not drop with initial treatment interventions (RRT and fluids)
• Renal impairment
• Vasopressor support (>0.1 μg/kg/min)
II-3 1
Mannitol or hypertonic saline should be administered for surges of ICP with consideration for short-term
hyperventilation (monitor reverse jugular venous saturation to prevent excessive hyperventilation and risk of
cerebral hypoxia). Mild hypothermia and indomethacin may be considered in uncontrolled ICH, the latter only in
the context of hyperaemic cerebral blood flow
II-2 1

19. ALF and RRT – is it only for AKI?
• 4080% of ALF patients referred to liver units have AKI
• Associated with increased mortality and longer hospital stays
• Increased age, paracetamol-induced ALI, SIRS, hypotension, and infection increase risk
Recommendations
Early institution of extracorporeal support (RRT) should be considered for persistent
hyperammonaemia, control of hyponatraemia and other metabolic abnormalities, fluid
balance and potentially temperature control
III 1
Anticoagulation of RRT circuits remain a matter of debate, and close monitoring of
metabolic status should be undertaken if citrate is utilized II-2 1
Continuous RRT should always be undertaken in critically ill patients with ALF, as opposed
to intermittent haemodialysis III 1

20. ASCITES
• Often precipitates by low albumin, Volume overload, and
infection
• Treat precipitating factor if identified
• Fluid and salt restriction
• Diuretics reserved for refractory cases or complications of
fluid overload
• Aggressive diuresis may precipitate HRS

21. ALF and infections
• The organisms most often implicated are gram-positive bacteria, presumably of skin origin.
• Gram-negative bacteria or a fungal infection is occasionally observed.
• Sepsis should be considered in any patient with fever, with or without any other signs of infection.
• Immune paralysis seen with advanced liver failure, symptoms may be subtle and fever may be absent.
• Accordingly, a high index of suspicion for sepsis should be maintained at all times
Recommendations
Prophylactic Antibiotics and antifungals have not been shown to improve survival in ALF II-2 1
Regular surveillance cultures should be performed in all patients III 1
Early anti-infection treatments should be introduced upon appearance of progression of
hepatic encephalopathy, clinical signs of infections, or elements of SIRS II-3 1
Antifungal therapy in those with prolonged critical care support for multiple organ failure
should
be considered*
II-3 1

22. Septic markers in liver failure

23. • Rapid changes in PT or INR are characteristic of ALF
• Significant prognostic value
• Common in ALF
• Thrombocytopenia
• Reduced circulating pro- and anti-coagulant proteins
• Increased PAI-1
• Abnormal coagulation does not translate to
increased risk of bleeding
• Most patients’ coagulation is normal despite
abnormal INR and PT
Coagulation: monitoring and management
1. Agarwal B, et al. J Hepatol 2012;57:780–6;
EASL CPG ALF. J Hepatol 2017;66:1047–81
0
1
2
Procoagulants
FII, FV, FVII, FIX,
FX, FXI, FXII, fibrinogen
Fold
change
in
anti-
and
procoagulants
in
ALF
within
first
48
hours
(multiples
of
normal
values)
Balanced relationship between reduced
procoagulants and anticoagulants
at admission to ICU with ALF1
-1
Anticoagulants
PC, PS, ATIII
VWF
FVIII

24. Recommendations
The routine use of fresh frozen plasma and other coagulation factors is not supported,
and should be limited to specific situations, such as insertion of ICP monitors or active bleeding
II-3 1
Haemoglobin target for transfusion is 7 g/dl II-2 1
Venous thrombosis prophylaxis should be considered in the daily review III 1
Prophylactic correction of coagulation or platelet levels is not necessary II-3 1

25. NAC in non acetaminophen poisoning

26. Forrest plot comparing mortality

27. EASL CPG ALF. J Hepatol 2017;66:1047–81

28. TPE in ALF

29. Artificial and bioartificial liver devices
*HVP defined as exchange of 8–12 or 15% of ideal body weight with fresh frozen plasma, for 3 days was superior to SMT regarding transplant-free and overall hospital
survival
Larsen FS, et al. J Hepatol. 2016;64:69–78; EASL CPG ALF. J Hepatol 2017;66:1047–81
• Liver-assist devices are intended to provide a ‘bridge’ to
LTx or recovery of liver function, reducing the need for
transplant
• Experience with ‘liver support devices’ to date has
been disappointing
• High-volume plasma exchange improved outcome in
an RCT in ALF*
Recommendations
Liver support systems (biological or adsorbent) should only be used in the context of RCTs II-1 1
Plasma exchange in RCTs has been shown to improve transplant-free survival in patients with
ALF and to modulate immune dysfunction I 1
Plasma exchange may be of greater benefit in patients who are treated early and who will not
ultimately undergo liver transplant I 2
Grade of evidence Grade of recommendation
0
0
20
14
40
60
80
100
28 42 56 70 84
Time (days)
Cumulative
proportion
surviving
(%)
7 21 35 49 63 77 91
HVP (n=92)
SMT (n=90)

30. Criteria for emergency liver transplantation
EASL CPG ALF. J Hepatol 2017;66:1047–81
Beaujon-Paul Brousse criteria (Clichy)
• Confusion or coma (HE stage 3 or 4)
• Factor V <20% of normal if age <30 years
or
• Factor V <30% if age >30 years
King’s College criteria
ALF due to paracetamol
• Arterial pH <7.3 after resuscitation and
>24 hours since ingestion
• Lactate >3 mmol/L or
• The 3 following criteria:
– HE >Grade 3
– Serum creatinine >300 µmol/L
– INR >6.5
ALF not due to paracetamol
• INR >6.5 or
• 3 out of 5 following criteria:
– Aetiology: indeterminate aetiology, hepatitis,
drug-induced hepatitis
– Age <10 years or >40 years
– Interval jaundice encephalopathy >7 days
– Bilirubin >300 µmol/L
– INR >3.5

31. Liver transplantation- only cure in irreversible

32. Prognostic markers

33. Summary and impact on current practice

34. References

35. Take home message
• Not all apheresis are same
• Early - the better
• Understand the molecule
• No method is superior
• Hypocalcaemia and anaphylaxis – to look for
• Category 3 – only if benefit outweigh risk and cost

36. Thank You